We introduce a method for analyzing small interfering RNA (siRNA) genetic screens based entirely on off-target effects. Using a screen for members of the Wnt pathway, we demonstrate that this method identifies known pathway components, some of which are not present in the screening library. This technique can be applied to siRNA screen results retroactively to confirm positives and identify genes missed using conventional methods for on-target gene selection.

BACKGROUND: Despite high rates of postcardiac surgery depression, studies of depression treatment in this population have been limited. OBJECTIVE: The aim of this study was to evaluate early cognitive behavioral therapy (CBT) in a home environment in patients recovering from cardiac surgery. METHODS: : From July 2006 through October 2009, we conducted a randomized controlled trial and enrolled 808 patients who were screened for depressive symptoms using the Beck Depression Inventory (BDI) in the hospital and 1 month later. Patients were interviewed using the Structured Clinical Interview for DSM-IV; those who met criteria for clinical depression (n = 81) were randomized to CBT (n = 45) or usual care (UC; n = 36). After completion of the UC period, 25 individuals were offered later CBT (UC + CBT). RESULTS: Main outcomes (depressive symptoms [BDI] and clinical depression [Structured Clinical Interview for DSM-IV]) were evaluated after 8 weeks using intention-to-treat principles and linear mixed models. Compared with the UC group, in the CBT group, there was greater decline in BDI scores (β = 1.41; 95% confidence interval [CI], 0.81-2.02; P = < .001) and greater remission of clinical depression (29 [64%] vs 9 [25%]; number need to treat, 2.5; 95% CI, 1.7-4.9; P < .001). Compared with the early CBT group (median time from surgery to CBT, 45.5 days) the later UC + CBT group (median time from surgery to CBT, 122 days) also experienced a reduction in BDI scores, but the group × time effect was smaller (β = 0.79; 95% CI, 0.10-1.47; P = .03) and remission rates between the 2 groups did not differ. CONCLUSIONS: Early home CBT is effective in depressed postcardiac surgery patients. Early treatment is associated with greater symptom reduction than similar therapy given later after surgery.

OBJECTIVE: To examine whether spouses of patients with severe sepsis are at increased risk for depression independent of the spouse's presepsis history, whether this risk differs by sex, and is associated with a sepsis patient's disability after hospitalization. DESIGN: Prospective longitudinal cohort study. SETTING: Population-based cohort of U.S. adults over 50 yrs old interviewed as part of the Health and Retirement Study (1993-2008). PATIENTS: Nine hundred twenty-nine patient-spouse dyads comprising 1,212 hospitalizations for severe sepsis. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was identified using a validated algorithm in Medicare claims. Depression was assessed with a modified version of the Center for Epidemiologic Studies Depression Scale. All analyses were stratified by gender. The prevalence of substantial depressive symptoms in wives of patients with severe sepsis increased by 14 percentage points at the time of severe sepsis (from 20% at a median of 1.1 yrs presepsis to 34% at a median of 1 yr postsepsis) with an odds ratio of 3.74 (95% confidence interval: 2.20, 6.37), in multivariable regression. Husbands had an 8 percentage point increase in the prevalence of substantial depressive symptoms, which was not significant in multivariable regression (odds ratio 1.90, 95% confidence interval 0.75, 4.71). The increase in depression was not explained by bereavement; women had greater odds of substantial depressive symptoms even when their spouse survived a severe sepsis hospitalization (odds ratio 2.86, 95% confidence interval 1.06, 7.73). Wives of sepsis survivors who were disabled were more likely to be depressed (odds ratio 1.35 per activities of daily living limitation of sepsis survivor, 95% confidence interval 1.12, 1.64); however, controlling for patient disability only slightly attenuated the association between sepsis and wives' depression (odds ratio 2.61, 95% confidence interval 0.93, 7.38). CONCLUSIONS: Older women may be at greater risk for depression if their spouse is hospitalized for severe sepsis. Spouses of patients with severe sepsis may benefit from greater support and depression screening, both when their loved one dies and when their loved one survives.

Neuronal excitation can be substantially modulated by alterations in metabolism, as evident from the anticonvulsant effect of diets that reduce glucose utilization and promote ketone body metabolism. We provide genetic evidence that BAD, a protein with dual functions in apoptosis and glucose metabolism, imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phosphoregulation of BAD and are independent of its apoptotic function. BAD modifications that reduce glucose metabolism produce a marked increase in the activity of metabolically sensitive K(ATP) channels in neurons, as well as resistance to behavioral and electrographic seizures in vivo. Seizure resistance is reversed by genetic ablation of the K(ATP) channel, implicating the BAD-K(ATP) axis in metabolic control of neuronal excitation and seizure responses.

We are well into the third decade of the HIV epidemic. While strides have been made in HIV prevention, rates for African American men who have sex with men (AAMSM) and young AAMSM continue to increase-perhaps indicating that traditional deficit-approaches of HIV prevention are not effective for all populations. Following a recent call to investigate the resiliency of young gay men, this study identifies sources of resilience and strength within the House and Ball communities, a subculture comprised primarily of AAMSM. The mixed-methods design included survey data (N = 263) collected at community events, interviews with Ball attendees and focus group data with House members. Survey data indicate a relationship between participating in the House and Ball communities and seeking support, acceptance and entertainment. Qualitative data validate these findings and provide detail on motivations for AAMSM to participate and the perceived benefits of participation. Findings are discussed in relation to building strengths-based interventions, using concepts of resiliency including shamelessness, social creativity, social support and volunteerism.

BACKGROUND AND PURPOSE: Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical events such as strokes and transient ischemic attacks (TIAs). Little is known regarding how PTSD triggered by medical events affects patients' adherence to medications. METHODS: We surveyed 535 participants, age ≥40 years old, who had at least 1 stroke or TIA in the previous 5 years. PTSD was assessed using the PTSD Checklist-Specific for stroke; a score ≥50 on this scale is highly specific for PTSD diagnosis. Medication adherence was measured using the 8-item Morisky scale. Logistic regression was used to test whether PTSD after stroke/TIA was associated with increased risk of medication nonadherence. Covariates for adjusted analyses included sociodemographics, Charlson comorbidity index, modified Rankin Scale score, years since last stroke/TIA, and depression. RESULTS: Eighteen percent of participants had likely PTSD (PTSD Checklist-Specific for stroke ≥50), and 41% were nonadherent to medications according to the Morisky scale. A greater proportion of participants with likely PTSD were nonadherent to medications than other participants (67% versus 35%, P<0.001). In the adjusted model, participants with likely PTSD were nearly 3 times more likely (relative risk, 2.7; 95% CI, 1.7-4.2) to be nonadherent compared with participants without PTSD (PTSD Checklist-Specific for stroke <25) even after controlling for depression, and there was a graded association between PTSD severity and medication nonadherence. CONCLUSION: PTSD is common after stroke/TIA. Patients who have PTSD after stroke or TIA are at increased risk for medication nonadherence.

Diffusion tensor imaging enables in vivo investigation of tissue cytoarchitecture through parameter contrasts sensitive to water diffusion barriers at the micrometer level. Parameters are derived through an estimation process that is susceptible to noise and artifacts. Estimated parameters (e.g., fractional anisotropy) exhibit both variability and bias relative to the true parameter value estimated from a hypothetical noise-free acquisition. Herein, we present the use of the simulation and extrapolation (SIMEX) approach for post hoc assessment of bias in a massively univariate imaging setting and evaluate the potential of a SIMEX-based bias correction. Using simulated data with known truth models, spatially varying fractional anisotropy bias error maps are evaluated on two independent and highly differentiated case studies. The stability of SIMEX and its distributional properties are further evaluated on 42 empirical diffusion tensor imaging datasets. Using gradient subsampling, an empirical experiment with a known true outcome is designed and SIMEX performance is compared to the original estimator. With this approach, we find SIMEX bias estimates to be highly accurate offering significant reductions in parameter bias for individual datasets and greater accuracy in averaged population-based estimates.

Small molecule chaperones are a promising therapeutic approach for the Lysosomal Storage Disorders (LSDs). Here, we report the discovery of a new series of non-iminosugar glucocerebrosidase inhibitors with chaperone capacity, and describe their structure activity relationship (SAR), selectivity, cell activity phamacokinetics.

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

PURPOSE: Disrupted sleep patterns in children with epilepsy and their parents are commonly described clinically. A number of studies have shown increased frequency of sleep disorders among pediatric epilepsy patients; however, few have characterized the association between epilepsy and parental sleep quality and household sleeping arrangements. The purpose of this study was to explore the effect of pediatric epilepsy on child sleep, parental sleep and fatigue, and parent-child sleeping arrangements, including room sharing and cosleeping. METHODS: Parents of children 2 to 10 years of age with and without epilepsy completed written questionnaires assessing seizure history, child and parent sleep, and household sleeping arrangements. Children's Sleep Habits Questionnaire (CSHQ) scores were used to evaluate sleep disturbances for the child. The Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) were used to evaluate parental sleep and fatigue, respectively. The Early Childhood Epilepsy Severity Scale (E-Chess) was used to assess epilepsy severity. KEY FINDINGS: One hundred five households with a child with epilepsy and 79 controls participated in this study. Households with a child with epilepsy reported increased rates of both parent-child room sharing (p < 0.001) and cosleeping (p = 0.005) compared to controls. Children with epilepsy were found to have greater sleep disturbance by total CSHQ score (p < 0.001) and the following subscores: parasomnias (p < 0.001), night wakings (p < 0.001), sleep duration (p < 0.001), daytime sleepiness (<0.001), sleep onset delay (p = 0.009), and bedtime resistance (p = 0.023). Parents of children with epilepsy had increased sleep dysfunction (p = 0.005) and were more fatigued (p < 0.001). Severity of epilepsy correlated positively with degree of child sleep dysfunction (0.192, p = 0.049), parental sleep dysfunction (0.273, p = 0.005), and parental fatigue (0.324, p = 0.001). Antiepileptic drug polytherapy was predictive of greater childhood sleep disturbances. Nocturnal seizures were associated with parental sleep problems, whereas room sharing and cosleeping behavior were associated with child sleep problems. Within the epilepsy cohort, 69% of parents felt concerned about night seizures and 44% reported feeling rested rarely or never. Finally, 62% of parents described decreased sleep quality and/or quantity with cosleeping. SIGNIFICANCE: Pediatric epilepsy can significantly affect sleep patterns for both the affected child and his or her parents. Parents frequently room share or cosleep with their child, adaptations which may have detrimental effects for many households. Clinicians must not only be attentive to the sleep issues occurring in pediatric patients with epilepsy, but also for the household as a whole. These data provide evidence of a profound clinical need for improved epilepsy therapeutics and the development of nocturnal seizure monitoring technologies.